Dehydroepiandrosterone (DHEA) effects on vascular function and peripheral insulin resistance in a menopause experimental model.

A administração de deidroepiandrosterona (DHEA) tem resultado em efeitos anti-diabetogênicos em animais de experimentação e no homem. Assim, o objetivo desse trabalho foi avaliar o efeito do DHEA sobre a função vascular em aorta e resistência periférica à insulina em roedores fêmeas ovariectomizadas (modelo experimental de menopausa - OVX). O tratamento com DHEA em ratas OVX, embora não levou a nenhuma alteração da composição corporal, induziu a uma redução na pressão arterial sistólica e disatólica, além de uma melhora na função vascular, aumentando a resposta à ACh e reduzindo a resposta à fenilefrina. Isso foi associado a uma redução do estresse oxidativo e inflação na aorta das ratos OVX. Para estudo da resistência à insulina foram utilizadas camundongos fêmeas OVX alimentadas com dieta hiperlipídica. O tratamento com DHEA nesses animais levou a uma redução do percentual de gordura corporal, provavelmente devido a uma redução da ingestão calórica. Também foi observado um aumento da sensibilidade à insulina nos animais tratados com DHEA, associado a uma redução do acúmulo ectópico de lipídios (fígado e músculo). Concluímos que o DHEA pode ser uma possível altenativa de tratamento, ao invés de estradiol, em mulheres na menopausa, já que ele é capaz de melhorar a função vascular e perfil metabólico em modelo experimental de menopausa.Dehydroepiandrosterone (DHEA) treatment has resulted in anti-diabetogenic effects in both animals and humans. The aim of this study was to evaluate the effect of DHEA on vascular function in the aorta and peripheral insulin resistance in ovariectomized female rodents (experimental model of menopause - OVX). Although DHEA treatment in OVX rats did not lead to any change in body composition, it induced a decrease in blood pressure, and an improvement in vascular function, increasing the ACh response and reduces the response to phenylephrine. This was associated with a reduction in oxidative stress and inflammation in the aorta of OVX rats. For the study of insulin resistance it was used OVX female mice fed with high fat diet. DHEA treatment in these animals led to a reduction in body fat percentage, probably due to a reduction in caloric intake. It was also observed an increase in insulin sensitivity in animals treated with DHEA, associated with a reduction in ectopic fat (liver and muscle) accumulation. We conclude that DHEA may be a possible alternative treatment instead of estradiol, in postmenopausal women, since he is able to improve vascular function and metabolic profile in an experimental model of menopause

Effect in vitro of dehydroepiandrosterone (DHEA) on IRS/PI3-K/Akt pathway and insulin secretion on rats pancreatic islets.

A administração de deidroepiandrosterona (DHEA) tem resultado em efeitos anti-diabetogênicos em animais de experimentação e no homem. Assim, o objetivo desse trabalho é avaliar o efeito do DHEA in vitro na expressão protéica do IR, do IRS-1, IRS-2, PI3-K, Akt, ERK-1/2; na expressão gênica do PDX-1, do PGC-1, da insulina, do GLUT-2 e da glicocinase; e avaliar a secreção estática de insulina de ilhotas pancreáticas de ratos. O cultivo das ilhotas por 24 horas com DHEA, não induziu nenhuma alteração tanto na expressão das proteínas quanto na secreção estática de insulina estimulada por glicose. Ocorreu aumento da fosforilação de ERK-1/2 e na expressão gênica do PGC-1. As células RINm5F, cultivadas por 72 horas com DHEA, apresentaram aumento da expressão total de IRS-1 e IRS-2. Concluímos, que 24 horas de cultura com ilhotas não é tempo suficiente para observar nenhuma alteração induzida pelo DHEA, na secreção de insulina, e na expressão das proteínas da via IRS/PI3-K/Akt. Células RINm5F podem ser um modelo alternativo para investigar os efeitos diretos do DHEA.The dehydroepiandrosterone (DHEA) administration has resulted in reduction of abdominal fat and protection against insulin resistance from experimental animals and humans. So, the purpose of this project is measure the in vitro effects from DHEA: on protein expression of insulin receptor, the proteins IRS-1, IRS-2, PI3-K, Akt, and ERK-1/2; on gene expression of transcriptional factors PDX-1 and PGC-1, insulin, glucose transport GLUT-2 and glicocinase; and to measure the static insulin secretion, on cultured pancreatic islets of the rat. The culture of pancreatic islet for 24 hours with DHEA, did not induce nothing alteration on protein expression of the IR, IRS-1, IRS-2, PI3-K, Akt-1 and ERK-1/2, and static insulin secretion induced by glucose. However, happened increase ERK-1/2 phosphorylation and PGC-1 gene expression. The RINm5F cells, cultured by 72 hours, showed increase of the IRS-1 and IRS-2 expression. We conclude that 24 hours of the pancreatic islets culture are not sufficient time to look any alteration induced by DHEA, on insulin secretion, and on protein expression involved on IRS/PI3-K/Akt pathway. RINm5F cells can be an alternative model to research the direct effects from DHEA

<b>DHEA and non-alcoholic fat liver disease: increased gene expression of peroxisome proliferation-activated receptor γ (PPARγ) and fatty acid synthase (FAS)

Dehydroespiandrosterone (DHEA) is associated with improvements in chronic degenerative diseases, including obesity, insulin resistance, and cardiovascular diseases. Nevertheless, it is observed an increase in its concentration in individuals with liver lipid infiltration, but it is not precise if this condition emerges as a cause or a consequence. In this way, we aimed to identify gene expression alterations in lipid and glucose liver metabolism markers, as well as oxidative stress markers. For this purpose, male Wistar rats, 12-14 months old were treated with subcutaneous injections of DHEA (only dose of 10 mg kg-1); and after 7 days, hepatic gene expression by PCR real time were performed for the following genes:  G6Pase, PEPCK, FAS, PPARγ, malic enzyme, ChREBP, LXR, catalase, GPx, iNOS, NADPH oxidase subunits and PCNA. We observed a tendency of reduction in G6Pase gene expression in treated group (p = 0.08). In addition, it was identified an increase in liver PPARγ and FAS gene expressions, two markers of increased activity of lipogenic pathway. We also observed an increase in iNOS gene expression, a known inductor of systemic and hepatic insulin resistance. In conclusion, our data indicates that the treatment with DHEA can be associated with the development of liver lipid infiltration and hepatic insulin resistance

Changes in food intake, metabolic parameters and insulin resistance are induced by an isoenergetic, medium-chain fatty acid diet and are associated with modifications in insulin signalling in isolated rat pancreatic islets

LLong-chain fatty acids are capable of inducing alterations in the homoeostasis of glucose-stimulated insulin secretion (GSIS), but the effect of medium-chain fatty acids (MCFA) is poorly elucidated. In the present study, we fed a normoenergetic MCFA diet to male rats from the age of 1 month to the age of 4 months in order to analyse the effect of MCFA on body growth, insulin sensitivity and GSIS. The 45% MCFA substitution of whole fatty acids in the normoenergetic diet impaired whole body growth and resulted in increased body adiposity and hyperinsulinaemia, and reduced insulin-mediated glucose uptake in skeletal muscle. In addition, the isolated pancreatic islets from the MCFA-fed rats showed impaired GSIS and reduced protein kinase Ba (AKT1) protein expression and extracellular signal-related kinase isoforms 1 and 2 (ERK(1/2)) phosphorylation, which were accompanied by increased cellular death. Furthermore, there was a mildly increased cholinergic sensitivity to GSIS. We discuss these findings in further detail, and advocate that they might have a role in the mechanistic pathway leading to the compensatory hyperinsulinaemic status found in this animal model.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES

Dehydroepiandrosterone protects against oxidative stress-induced endothelial dysfunction in ovariectomized rats

Cardiovascular disease is less frequent in premenopausal women than in age-matched men or postmenopausal women. Moreover, the marked age-related decline in serum dehydroepiandrosterone (DHEA) level has been associated to cardiovascular disease. The aim of this study was to evaluate the effects of DHEA treatment on vascular function in ovariectomized rats. At 8 weeks of age, female Wistar rats were ovariectomized (OVX) or sham (SHAM) operated and 8 weeks after surgery both groups were treated with vehicle or DHEA (10 mg kg-1 week-1) for 3 weeks. Aortic rings were used to evaluate the vasoconstrictor response to phenylephrine (PHE) and the relaxation responses to acetylcholine (ACh) and sodium nitroprusside (SNP). Tissue reactive oxygen species (ROS) production and SOD, NADPH oxidase and eNOS protein expression were analysed. PHE-induced contraction was increased in aortic rings from OVX compared to SHAM, associated with a reduction in NO bioavailability. Furthermore, the relaxation induced by ACh was reduced in arteries from OVX, while SNP relaxation did not change. The incubation of aortic rings with SOD or apocynin restored the enhanced PHE-contraction and the impaired ACh-relaxation only in OVX. DHEA treatment corrected the increased PHE contraction and the impaired ACh-induced relaxation observed in OVX by an increment in NO bioavailability and decrease in ROS production. Besides, DHEA treatment restores the reduced Cu/Zn-SOD protein expression and eNOS phosphorylation and the increased NADPH oxidase protein expression in the aorta of OVX rats. The present results suggest an important action of DHEA, improving endothelial function in OVX rats by acting as an antioxidant and enhancing the NO bioavailability.FAPESPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)CNPq, Brazi